Effect of selective percutaneous myofascial lengthening and functional physiotherapy on walking in children with cerebral palsy: Three-dimensional gait analysis assessment.

BACKGROUND: Walking is the most affected motor function in children with cerebral palsy (CP). Orthopaedic surgery is regularly used to improve ambulation in children with CP. Selective Percutaneous Myofascial Lengthening (SPML) is considered the state-of-the art technique for surgical lengthening of spastic/contracted muscles in CP. The purpose of this study was to investigate the effect of combined SPML surgery and postoperative functional physiotherapy on gait function and characteristics of children with spastic cerebral palsy (CP). METHODS: Twenty-six children with spastic CP, aged 5-7 years, Gross Motor Function Classification System (GMFCS) levels II (n = 6), III (n = 12) and IV (n = 8) participated in a quasi-experimental one-group pretest-posttest study with a 9-month follow-up. The Global Motion Graph Deviation Index (MGDI) (including MGDI sub-indices of each joint in each plane of motion) and spatiotemporal parameters of a three-dimensional kinematic gait analysis were used to assess the gait function and characteristics, respectively. RESULTS: Nine months following SPML and functional physiotherapy, statistically significant improvements (p < 0.05) were noted in the Global MGDI, the MGDIs of sagittal plane knee and ankle motion analysis graphs, and the four most common spatiotemporal measures of gait: walking velocity, stride length, step length, and cadence. CONCLUSION: Children with spastic CP seem to gain better overall gait function following SPML procedure and functional physiotherapy, by achieving higher walking velocity, longer stride length and step length, and faster cadence. Further studies with control group and longer follow-up three-dimensional gait analyses are warranted to validate these positive results.

Structural mapping of GABRB3 variants reveals genotype-phenotype correlations.

PURPOSE: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. METHODS: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. RESULTS: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. CONCLUSION: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.

Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation.

PURPOSE: Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment. METHODS: Retrospective case series of 20 patients. RESULTS: Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients. CONCLUSION: We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.

Temporal lobe "plus" epilepsy associated with oligodendroglial hyperplasia (MOGHE).

BACKGROUND: Mild malformation of cortical dysplasia (mMCD) with oligodendroglial hyperplasia (MOGHE) is an epilepsy-related pathologic entity highlighted in post-surgical specimens of frontal lobe epilepsy (FLE) patients. AIMS OF THE STUDY: We present two temporal lobe epilepsy (TLE) cases with MOGHE and discuss clinical, neurophysiological, and neuroimaging features that may be indicative of surgical outcome. METHODS: We identified two cases with MOGHE out of 30 temporal lobe epilepsy (TLE) surgical patient cohort, whose pathological distribution spared the hippocampal structures. RESULTS: The TLE cases shared common features with the FLE series in terms of patient profiles, MRI findings and post-surgical outcome. TLE plus seizure semiology combined with extratemporal scalp electroencephalographic (EEG) and electrocorticographic (ECoG) epileptiform elements at a distance from the imaging lesion were suggestive of an underlying multifocal pathology. CONCLUSIONS: MOGHE pathology has to be considered in the decision-making process for TLE epilepsy surgery when this constellation of features is met.

Osteoporosis-pseudoglioma syndrome: clinical, genetic, and treatment-response study of 10 new cases in Greece.

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal-recessive disorder, characterized by severe osteoporosis and early-onset blindness. Loss of function mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5) have been established as the genetic defect of the disease. We report the clinical and genetic evaluation of ten OPPG cases in eight related nuclear families and their close relatives. Bone mineral density (BMD) in OPPG patients was assessed by dual-energy X-ray absorptiometry (DXA). Genotyping of LRP5 gene and targeted detection of index mutation were performed by DNA direct sequencing. Four patients were introduced to bisphosphonates. Mutational screening of LRP5 gene revealed the c.2409_2503+79del deletion in homozygous state, expected to result in a truncated protein. Among 44 members of the pedigree, 10 (22%) were identified homozygous and 34 (59%) heterozygous for this mutation. All patients had congenital blindness and 7 of them had also impaired bone mineral density. Four of them received bisphosphonates and responded with decreased bone pain and improvement in BMD; however, 3 patients presented with one fracture during treatment.Conclusion: The current study presents the molecular and clinical profiles of 10 new OPPG cases, being part of an extended pedigree. Patients who received bisphosphonate treatment responded well with increase in their BMD, though fractures occurred during therapy. What is known: • OPPG syndrome is a rare genetic disorder characterized by congenital blindness and juvenile osteoporosis. • Loss of function mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5) is the genetic defect of the disease. What is new: • Genetic and clinical phenotype of 10 new OPPG patients. • The ten new OPPG patients presented with phenotypical variability in osseous manifestations.

Single amino acid loss in the dystrophin protein associated with a mild clinical phenotype.

INTRODUCTION: The dystrophinopathies include a spectrum of muscle diseases caused by mutations in the dystrophin (DMD) gene. The clinical phenotype ranges from severe Duchenne muscular dystrophy to a mild phenotype with elevated creatine kinase (CK). METHODS: Clinical and molecular assessment of 7 patients carrying a single amino acid loss in the dystrophin protein (p.His1690del) caused by a c.5068_5070delCAC tri-nucleotide deletion in exon 36 of the DMD gene. RESULTS: All patients were asymptomatic or oligosymptomatic and had elevated CK levels. Febrile illness, but not exercise, induced muscle symptoms in some patients. None had evidence of cardiomyopathy. Analysis of the short tandem repeat (STR)45 locus and sequencing of exon 36 of the DMD gene indicates that c.5068_5070delCAC is a founder mutation. CONCLUSIONS: The c.5068_5070delCAC locus in the DMD gene is associated with a very mild phenotype. Further study is needed to evaluate disease progression in these patients. Muscle Nerve 55: 46-50, 2017.

Changes in Lower Extremity Passive Range of Motion and Muscle Strength After Selective Percutaneous Myofascial Lengthening and Functional Physiotherapy in Children With Cerebral Palsy.

Background Children with cerebral palsy (CP) often experience motor and postural disorders, along with spasticity, muscle weakness, muscle-tendon contractures, and decreased joint range of motion (ROM). Muscle-tendon contractures are typically addressed through orthopaedic surgery to improve joint ROM, which can result in further muscle weakness. This study aimed to investigate the impact of selective percutaneous myofascial lengthening (SPML) combined with functional physiotherapy on joint passive ROM and isometric muscle strength in the lower extremities of children with spastic CP. Methods A single-group pre- and post-test design was utilised in this study. Twenty-six children aged five to seven years with spastic CP and Gross Motor Function Classification System levels II-IV underwent the SPML procedure and received nine months of postoperative functional strength training physiotherapy. Joint passive ROM and isometric muscle strength were measured using a universal goniometer and a digital hand-held dynamometer, respectively. Paired-sample t-tests were conducted to compare baseline and follow-up measurements. Results Significant improvements (p < 0.05) were observed in passive ROM of hip abduction, straight leg raise, popliteal angle, and ankle dorsiflexion, as well as in isometric strength of hip flexors, extensors, abductors and adductors, knee extensors, and ankle dorsiflexors. Conclusions The SPML procedure supported by postoperative functional physiotherapy can effectively address fixed contractures by significantly increasing passive joint ROM and muscle strength. Further research with longer-term follow-up measurements is necessary to confirm and expand upon these findings.

Specific Gut Microbiome Signatures in Children with Cow's Milk Allergy.

Although gut dysbiosis is associated with cow's milk allergy (CMA), causality remains uncertain. This study aimed to identify specific bacterial signatures that influence the development and outcome of the disease. We also investigated the effect of hypoallergenic formula (HF) consumption on the gut microbiome of milk-allergic children. 16S rRNA amplicon sequencing was applied to characterize the gut microbiome of 32 milk-allergic children aged 5-12 years and 36 age-matched healthy controls. We showed that the gut microbiome of children with CMA differed significantly from that of healthy children, regardless of whether they consumed cow's milk. Compared to that of healthy cow's milk consumers, it was depleted in Bifidobacterium, Coprococcus catus, Monoglobus, and Lachnospiraceae GCA-900066575, while being enriched in Oscillibacter valericigenes, Negativibacillus massiliensis, and three genera of the Ruminococcaceae family. Of these, only the Ruminococcaceae taxa were also enriched in healthy children not consuming cow's milk. Furthermore, the gut microbiome of children who developed tolerance and had received an HF was similar to that of healthy children, whereas that of children who had not received an HF was significantly different. Our results demonstrate that specific gut microbiome signatures are associated with CMA, which differ from those of dietary milk elimination. Moreover, HF consumption affects the gut microbiome of children who develop tolerance.

Combined exome analysis and exome depth assessment achieve a high diagnostic yield in an epilepsy case series, revealing significant genomic heterogeneity and novel mechanisms.

OBJECTIVES: Genetics of epilepsy are highly heterogeneous and complex. Lesions detected involve genes encoding various types of channels, transcription factors, and other proteins implicated in numerous cellular processes, such as synaptogenesis. Consequently, a wide spectrum of clinical presentations and overlapping phenotypes hinders differential diagnosis and highlights the need for molecular investigations toward delineation of underlying mechanisms and final diagnosis. Characterization of defects may also contribute valuable data on genetic landscapes and networks implicated in epileptogenesis. METHODS: This study reports on genetic findings from exome sequencing (ES) data of 107 patients with variable types of seizures, with or without additional symptoms, in the context of neurodevelopmental disorders. RESULTS: Multidisciplinary evaluation of ES, including ancillary detection of copy number variants (CNVs) with the ExomeDepth tool, supported a definite diagnosis in 59.8% of the patients, reflecting one of the highest diagnostic yields in epilepsy. CONCLUSION: Emerging advances of next-generation technologies and 'in silico' analysis tools offer the possibility to simultaneously detect several types of variations. Wide assessment of variable findings, specifically those found to be novel and least expected, reflects the ever-evolving genetic landscape of seizure development, potentially beneficial for increased opportunities for trial recruitment and enrollment, and optimized, even personalized, medical management.

Genetic spectrum of hereditary neuropathies with onset in the first year of life.

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset.

Erythromelalgia in an Adolescent Female.

Erythromelalgia is a disabling syndrome of paroxysmal vasodilation affecting the feet, hands and face characterised by patient's cooling behaviour to achieve symptom relief. It can be primary or secondary and although a rare disorder it has been described in children and adolescents. We describe the case of a 14-year-old female diagnosed with primary erythromelalgia successfully treated with aspirin, amitriptyline, and carbamazepine.

The Greek Version of Mini-Manual Ability Classification System (Mini-MACS): Translation and Reliability Study.

INTRODUCTION: The Mini-Manual Ability Classification System (Mini-MACS) is an adaptation of the MACS for children with cerebral palsy (CP) aged 1-4 years, which classifies children's performance to handle objects that are relevant to their age and development. The availability of a reliable Mini-MACS in Greek would allow for using it safely and properly in the clinical and research context of Greece. Therefore, the purpose of this study was to translate the original English version into Greek and examine its test-retest and interrater reliability. MATERIAL AND METHODS: The English Mini-MACS was translated into Greek using the "forward-backward" method. Sixty-three children with CP, Gross Motor Function Classification System (GMFCS) levels I-V, aged 12 -50 months were included in the reliability study. Test-retest and interrater reliability were assessed using the interclass correlation coefficient (ICC). The association between Mini-MACS and GMFCS level ratings was also assessed using Spearman's rho correlation coefficient (ρ). RESULTS: The translated version was easy to understand and use. The Greek Mini-MACS was found to have excellent test-retest reliability (ICC > 0.96) for both parents and therapists, good interrater reliability (ICC=0.89) between therapists and parents, and moderate-to-strong correlation with the GMFCS (ρ = 0.56-0.64, p < 0.0001). CONCLUSION: The Greek Mini-MACS constitutes a user-friendly and reliable scale for use in the Greek population.

Translation, reliability and validity of the Greek functional mobility scale (FMS) for children with cerebral palsy.

PURPOSE: To translate and investigate the reliability and validity of the Greek version of the Functional Mobility Scale (FMS). METHODS: FMS was translated into Greek. Test-retest reliability (Cohen's weighted kappa coefficient, κw) and concurrent validity (Spearman's rank correlation coefficient, rs) of the Greek version of FMS were assessed in children with Cerebral Palsy (CP). Sixty children (mean age 7.82 ± 3.20 years) were recruited. Physical therapists administered the FMS by interviewing parents about their children's mobility status. The Gross Motor Function Classification System (GMFCS) was additionally used for testing concurrent validity. RESULTS: The translation of the FMS was deemed easy to understand and administer. The Greek FMS was demonstrated to have almost perfect test-retest reliability (κw=0.98-1.00), and very strong correlation with the GMFCS (-0.85 ≤ rs ≤ -0.89, p < 0.001). CONCLUSIONS: The Greek version of the FMS was shown to be a reliable and valid classification system for CP and can be used with confidence by Greek physical therapists.Implications for rehabilitationThe FMS provides a very simple and practical outcome measure of functional mobility in children with CP.The use of the reliable and valid Greek FMS will enhance the physical therapy assessment process in the Greek population, by offering the feasibility to detect the motor performance changes in children with CP as they grow or following interventions.The current study renders the Greek FMS available for utilization by physical therapists in order to quantify the independent mobility in children with CP.

The clinical spectrum of SMA-PME and in vitro normalization of its cellular ceramide profile.

OBJECTIVE: The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement. METHODS: Clinical features of 6 patients with SMA-PME were assessed by retrospective chart review, and a literature review of 24 previously published cases was performed. Leukocyte enzyme activity of acid ceramidase was assessed with a fluorescence-based assay. Skin fibroblast ceramide content and was assessed by high performance liquid chromatography, electrospray ionization tandem mass spectroscopy. Enzyme replacement was assessed using recombinant human acid ceramidase (rhAC) in vitro. RESULTS: The six new patients showed the hallmark features of SMA-PME, with variable initial symptom and age of onset. Five of six patients carried at least one of the recurrent SMA-PME variants observed in two specific codons of ASAH1. A review of 30 total cases revealed that patients who were homozygous for the most common c.125C > T variant presented in the first decade of life with limb-girdle weakness as the initial symptom. Sensorineural hearing loss was associated with the c.456A > C variant. Leukocyte acid ceramidase activity varied from 4.1%-13.1% of controls. Ceramide species in fibroblasts were detected and total cellular ceramide content was elevated by 2 to 9-fold compared to controls. Treatment with rhAC normalized ceramide profiles in cultured fibroblasts to control levels within 48 h. INTERPRETATION: This study details the genotype-phenotype correlations observed in SMA-PME and shows the impact of rhAC to correct the abnormal cellular ceramide profile in cells.

The PURPLE N study: objective and perceived nutritional status in children and adolescents with cerebral palsy.

PURPOSE: To obtain information on characteristics, management, current objective nutritional status and perception of nutritional status of children with cerebral palsy (CP) from healthcare professionals (HCPs) and caregivers. MATERIALS AND METHODS: A detailed survey of several items on eight main topics (general characteristics, motor function, comorbidities, therapies, anthropometry, feeding mode and problems and perceived nutritional status) was developed and tested for the study. Correlation between nutritional status and Gross Motor Function Classification System (GMFCS) levels was assessed using continuous variables (Z-scores for weight-for-age, height-for-age, weight-for-height, and body mass index-for-age), and categorical variables (being malnourished, stunted, or wasted). HCP and caregiver perceptions of the child's nutritional status as well as agreement between perceived and objective nutritional status and agreement between perceived nutritional status and concerns about the nutritional status were analyzed. RESULTS: Data were available for 497 participants from eight European countries. Poorer nutritional status was associated with higher (more severe) GMFCS levels. There was minimal agreement between perceived and objective nutritional status, both for HCPs and caregivers. Agreement between HCP and caregiver perceptions of the child's nutritional status was weak (weighted kappa 0.56). However, the concerns about the nutritional status of the child were in line with the perceived nutritional status. CONCLUSIONS: The risk of poor nutritional status is associated with more severe disability in children and adolescents with CP. There is a mismatch between HCP and caregiver perceptions of participants' nutritional status as well as between subjective and objective nutritional status. Our data warrant the use of a simple and objective screening tool in daily practice to determine nutritional status in children and adolescents with CP. Clinical trial registration: ClinicalTrials.gov Identifier: NCT03499288 (https://clinicaltrials.gov/ct2/show/NCT03499288). IMPLICATIONS FOR REHABILITATIONUse of the ESPGHAN recommendations and simple screening tools in daily practice is needed to improve nutritional care for individuals with CP.Attention should be paid to the differences in the perception of nutritional status of individuals with CP between professionals and caregivers to improve appropriate referral for nutritional support.Objective measures rather than the professional's perception need to be used to define the nutritional status of individuals with CP.

Effects of measles-containing vaccination in children with severe underlying neurologic disease.

BACKGROUND: Measles outbreaks pose significant risk for those unvaccinated. PATIENTS AND METHODS: Measles-containing vaccine was offered to unvaccinated children with severe neurologic diseases during a measles outbreak. Vaccination adverse events were reported by parents 30 days following vaccination. Long term effects were evaluated 12 months post vaccination. RESULTS: Twenty-seven children were vaccinated (36 doses given). Half of parents (51.8%) reported no adverse events following immunization. Adverse events included afebrile seizures (6/36), fever alone (5/36) and febrile seizures (5/36). Two children required hospitalization. Quadrivalent measles-containing vaccine combined with varicella was associated with febrile seizures (p = 0.04). No child needed adjustment of the anti-epileptic treatment or exhibited developmental regression. CONCLUSION: Ina series of children with prior severe neurologic disease, the safety-tolerability profile ofvaccines containing a measles vaccine component suggests that vaccination is justified. Main side effect was seizure aggravation in children with known epileptic disease.

Effects of minimally invasive surgery and functional physiotherapy on motor function of children with cerebral palsy: A non-randomised controlled trial.

PURPOSE: This non-randomised controlled trial investigated whether a combined programme of functional physiotherapy and minimally invasive orthopaedic surgery improves the level and degree of capacity and performance of gross motor function in children with spastic cerebral palsy (CP). METHODS: Fifty-two children with spastic CP aged 5-7 years, Gross Motor Function Classification System (GMFCS) levels II-IV, were allocated to two equal groups: experimental group (selective percutaneous myofascial lengthening [SPML] procedure and 9-month functional strengthening physiotherapy programme) and control (standard physiotherapy) groups. At baseline and at the end of the 9-month intervention, the capacity and performance of gross motor function were assessed with the Gross Motor Function Measure (GMFM) D and E subcategories and Functional Mobility Scale (FMS), respectively. The level of gross motor function was measured with the GMFCS. RESULTS: There was a statistically significant difference in the post-intervention improvements in the GMFM D (experimental mean difference = 19.63 ± 10.46; control mean difference = 2.40 ± 4.62) and E (experimental mean difference = 19.33 ± 11.82; control mean difference = 4.20 ± 6.26) between experimental and control group (p < 0.001). There was a significant improvement in the GMFCS level and each FMS distance for the experimental group (p < 0.001), but not for the control group (p > 0.05). CONCLUSION: SPML procedure combined with functional physiotherapy improves gross motor function in children with spastic CP, by raising the degree and level of motor independence.

Genetic cause of epilepsy in a Greek cohort of children and young adults with heterogeneous epilepsy syndromes.

We describe a cohort of 10 unrelated Greek patients (4 females, 6 males; median age 6.5 years, range 2-18 years) with heterogeneous epilepsy syndromes with a genetic basis. In these patients, causative genetic variants, including two novel ones, were identified in 9 known epilepsy-related genes through whole exome sequencing. A patient with glycine encephalopathy was a compound heterozygote for the p.Arg222Cys and the p.Ser77Leu AMT variant. A patient affected with Lafora disease carried the homozygous p.Arg171His EPM2A variant. A de novo heterozygous variant in the GABRG2 gene (p.Pro282Thr) was found in one patient and a pathogenic variant in the GRIN2B gene (p.Gly820Val) in another patient. Infantile-onset lactic acidosis with seizures was associated with the p.Arg446Ter PDHX gene variant in one patient. In two additional epilepsy patients, the p.Ala1662Val and the novel non-sense p.Phe1330Ter SCN1A gene variants were found. Finally, in 3 patients we observed a novel heterozygous missense variant in SCN2A (p.Ala1874Thr), a heterozygous splice site variant in SLC2A1 (c.517-2A>G), as a cause of Glut1 deficiency syndrome, and a pathogenic variant in STXBP1 (p.Arg292Leu), respectively. In half of our cases (patients with variants in the GRIN2B, SCN1A, SCN2A and SLC2A1 genes), a genetic cause with potential management implications was identified.

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.